The mouse model of atherosclerosis can be used to identify novel genes that affect atherosclerosis susceptibility. Non-lipid risk factors are important in heart disease but it is difficult to identify the genes that underlie such factors. One approach to identifying such factors to clone the genes underlying atherosclerosis differences between mouse strains that can not be explained by the lipid profiles. Ath8 is such a gene; it is the major determinant of the atherosclerosis susceptibility difference between inbred strains NZB/BINJ (NZB) and SM/J (SM). Although strains NZB and SM differ in HDL-cholesterol and VLDL-LDL cholesterol, Ath8 affects atherosclerosis independently of these lipoprotein differences. The identify of the Ath8 gene product may therefore provide insights into the non-lipid factors that affect heart disease risk. Ath8 was mapped recent in our laboratory using quantitative trait loci mapping techniques. We propose to positionally clone Ath8. Because Ath8 was mapped in a relatively small cross, the chromosomal region containing the gene is large, approximately 28 cM. Therefore, the first step in cloning this gene will be to narrow the region by three sequential mouse crosses. Once the region is sufficiently narrowed, a DNA contig will be constructed and a complete transcript map of all genes in the region obtained. Transcripts will be evaluated by expression patter and function, if known. Candidate genes will be tested by sequence the cDNA from both strains or by expression differences between the strains. Finally, the most compelling candidate gene will be tested by transgenic rescue of the phenotype or construction of a knockout with a resulting change in atherosclerosis phenotype.